artikel ilmiah #2 17.01 Practical Preventive Therapy for Tuberculosis? Every new episode of tuberculosis — there were 9 million in 2010 — follows a period of asymptomatic infection lasting from weeks to decades. These subclinical infections, which are detectable with a tuberculin skin test or interferon- release assay, offer a target for prophylactic treatment either with drugs or, potentially, a vaccine. Vaccination after infection is not yet an option, but drug treatment has been available for 60 years in the form of 6 to 12 months of isoniazid preventive therapy (IPT), which protects up to 90% of infected persons from active tuberculosis. And yet very few tuberculosis-control programs have successfully carried out IPT on a large scale or even as a targeted treatment for persons at especially high risk for tuberculosis, such as children, contacts of persons with infectious cases, patients with human immunodeficiency virus (HIV) infection, or migrants from countries in which tuberculosis is highly endemic.

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The limited success of IPT is due to a combination of the patients' choice and public-health priorities. Infected but asymptomatic persons who have a small chance of progressing to active tuberculosis are often resistant to taking a drug every day for up to 12 months, risking hepatitis and other side effects. Operationally, program managers know that it would be hard to ensure adherence to the lengthy treatment regimen. Furthermore, IPT is less cost-effective than treating patients with active tuberculosis. The reason is that although isoniazid is cheap, hundreds of infected persons must be treated to prevent one case of tuberculosis. Chemotherapy for active tuberculosis, the principal control strategy today, is comparatively cost-effective but far from ideal. At the patient level, we wait for infections to progress to a potentially fatal, infectious illness for which treatment is not always successful. At the population level, the rate of reduction in the incidence of tuberculosis under chemotherapy is constrained by long periods of latency. Even in the best control programs, in which infection is diagnosed early and with high cure rates, it is not feasible to cut the incidence of tuberculosis by more than about 10% per year. Present evidence suggests that the control programs now operating in most high-burden countries, despite successes in elevating cure rates and reducing mortality, are achieving much less than 10% per year. To compound the problem, as the incidence of tuberculosis falls, the rate of decline slows because growing numbers of cases are developing from old infections. The upshot is that a direct attack on latent infection will be needed before we can think about the elimination of tuberculosis. The latest in a series of investigations of shorter preventive regimens is presented in this issue of the Journal. Sterling et al. carried out a randomized trial of the efficacy of 3 months of isoniazid plus rifapentine combination therapy, given once a week under supervision, as compared with 9 months of daily, self-administered isoniazid alone. This was a noninferiority trial because the efficacy of isoniazid alone in preventing active tuberculosis is already high; the main question was whether efficacy and effectiveness would be at least as good with the shorter, more easily supervised regimen. Because the study evaluated high-efficacy treatments in four low-incidence countries (Brazil, Canada, Spain, and the United States), there were few cases in either of the two well-matched groups in the trial. During 33 months of follow-up in 7731 subjects, an intention-to-treat effectiveness analysis counted 7 cases of tuberculosis in the combination-therapy group and 15 in the isoniazid-only group, for cumulative incidence rates of 0.19% and 0.43%, respectively, and a hazard ratio of 0.38 (95% confidence interval, 0.15 to 0.99). Because intention-to-treat analysis confounds adherence with therapeutic efficacy (better adherence was expected and observed in the shorter, supervised combination-therapy group), Sterling et al. rightly present a per-protocol efficacy analysis, inevitably yielding a smaller difference between the two study groups. However, both analyses showed that combination therapy tended to be superior to isoniazid alone and was clearly not inferior. In the combination-therapy group, fewer patients had hepatotoxicity, as expected from the lower total dose of isoniazid, but hypersensitivity was more commonly associated with the combination of isoniazid plus rifapentine. The findings of this trial, performed in low-incidence countries, suggest that isoniazid plus rifapentine is as good as the principal competing regimens — notably, 3 months of isoniazid plus rifampin or 4 months of rifampin monotherapy in places where the use of isoniazid is not recommended. However, a head-to-head comparison of these three options remains to be performed. Preventive therapy has the potential to deliver greater health benefits in high-incidence countries. In this context, a critical question for the isoniazid-plus-rifapentine regimen is whether 3 months of treatment will provide protection for longer than 2 to 3 years. Evidence from other studies has suggested that it might be adequate for HIV-negative persons but not for those with HIV infection. In a population of Alaskan Inuit living under intense transmission of tuberculosis (before the HIV era), a course of IPT was strongly protective for at least a decade. In contrast, recent studies of HIV-positive patients in Botswana and South Africa have reinforced the earlier finding that the incidence of tuberculosis increases soon after the discontinuation of IPT. In Botswana, the incidence of tuberculosis was more than 10% per year soon after the discontinuation of IPT, presumably because of the reactivation of residual infection, supplemented by reinfection. Would combination therapy with isoniazid plus rifapentine have to be given continuously and under supervision to protect HIV-positive or HIV-negative persons from reactivation or reinfection? A long-term study in a high-incidence setting is needed to find out.

artikel ilmiah #1 16.49 Aortic Stenosis The aorta is the main artery carrying blood out of the heart. When blood leaves the heart, it flows through the aortic valve, into the aorta. In aortic stenosis, the aortic valve does not open fully. This decreases blood flow from the heart.

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Causes

As the aortic valve becomes more narrow, the left ventricle has to increase pressure to pump blood out through the valve. To do this extra work, the muscles in the ventricle walls become thicker, which can lead to chest pain. As the pressure continues to rise, blood may back up into the lungs. Severe forms of aortic stenosis prevent enough blood from reaching the brain and the rest of the body. Aortic stenosis may be present from birth (congenital), but usually it develops later in life (is acquired). Children with aortic stenosis may have other congenital conditions. In adults, aortic stenosis usually occurs due to calcium deposits that narrow the valve. This is called calcific aortic stenosis, and it generally affects older people. The other common cause is rheumatic fever, a condition that may develop after strep throat or scarlet fever. Valve problems do not develop for 5 - 10 years or longer after rheumatic fever occurs. Rheumatic fever is increasingly rare in the United States. Calcification of the valve happens sooner in patients who are born with abnormal aortic or bicuspid valves. In rare cases, calcification can also occur more quickly in patients who have received radiation treatment to the chest. Aortic stenosis is not very common. It occurs more often in men than in women. Symptoms

People with aortic stenosis may have no symptoms until late in the course of the disease. The diagnosis may have been made when the health care provider heard a heart murmur and performed tests. Symptoms of aortic stenosis include: Breathlessness with activity Chest pain, angina-type Crushing, squeezing, pressure, tightness Pain increases with exercise, is relieved with rest Pain is felt under the chest bone but may move to other areas, most often the left side of the chest Fainting, weakness, or dizziness with activity Sensation of feeling the heart beat (palpitations) In infants and children, symptoms include: Becoming easily tired with exertion (in mild cases) Failure to gain weight Poor feeding Serious breathing problems that develop within days or weeks of birth (in severe cases) Children with mild or moderate aortic stenosis may get worse as they get older. They also run the risk of developing a heart infection (bacterial endocarditis). Exams and Tests

The health care provider will be able to feel a vibration or movement when placing a hand over the heart. A heart murmur, click, or other abnormal sound is almost always heard through a stethoscope. There may be a faintpulse or changes in the quality of the pulse in the neck (this is called pulsus parvus et tardus). Blood pressure may be low. The following tests may be performed: Chest x-ray Doppler echocardiography ECG Exercise stress testing Left cardiac catheterization MRI of the heart Transesophageal echocardiogram (TEE) Treatment

If there are no symptoms or symptoms are mild, you may only need to be monitored by a health care provider. Anyone with aortic stenosis should be monitored with a health history, physical exam, and an echocardiogram (heart ultrasound). People with severe aortic stenosis are usually told not to play competitive sports, even if they don't have symptoms. If symptoms do occur, strenuous activity must be limited. Medications are used to treat symptoms of heart failure or abnormal heart rhythms (most commonly atrial fibrillation). These include diuretics (water pills), nitrates, and beta-blockers. High blood pressure should also be treated. If aortic stenosis is severe, this treatment must be done carefully so blood pressure does not drop to dangerously low levels. In the past, most patients with heart valve problems were given antibiotics before dental work or an invasive procedure such as colonoscopy. The antibiotics were given to prevent an infection of the damaged heart. However, antibiotics are now used much less often before dental work and other procedures. Check with your health care provider to find out whether you need antibiotics. Patients should stop smoking and be treated for high cholesterol. Surgery to repair or replace the valve is the preferred treatment for adults or children who develop symptoms. Even if symptoms are not very bad, the doctor may recommend surgery based on test results. A less invasive procedure called balloon valvuloplasty may be done instead of surgery. A balloon is placed into an artery in the groin, threaded to the heart, placed across the valve, and inflated. However, narrowing often occurs again after this procedure. A newer procedure done at the same time as valvuloplasty can implant an artificial (prosthetic) valve. This procedure is usually done only in patients who cannot have surgery. Some children may need aortic valve repair or replacement. Children with mild aortic stenosis may be able to participate in most activities and sports. Outlook (Prognosis)

Without surgery, a person with aortic stenosis who has angina, fainting (syncope), or signs of heart failure will usually do poorly. Aortic stenosis can be cured with surgery. After surgery there is a risk for irregular heart rhythms, which can cause sudden death, and blood clots, which can cause a stroke. There is also a risk that the new valve will develop problems (become narrowed or leaky) and will need to be replaced. Possible Complications

Angina (chest pain) Arrhythmias Endocarditis Fainting (syncope) Left-sided heart failure Left ventricular hypertrophy (heart wall thickening) caused by the extra work of pushing blood through the narrowed valve When to Contact a Medical Professional

Call your health care provider if you or your child has symptoms of aortic stenosis. For example, call if you or your child has a sensation of feeling the heart beat (palpitations) for more than a short period of time. Also contact your doctor immediately if you have been diagnosed with this condition and your symptoms get worse or new symptoms develop. Alternative Names